Imine Reductase‐Catalyzed Enantioselective Reduction of Bulky α,β‐Unsaturated Imines en Route to a Pharmaceutically Important Morphinan Skeleton,Advanced Synthesis & Catalysis

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Imine Reductase‐Catalyzed Enantioselective Reduction of Bulky α,β‐Unsaturated Imines en Route to a Pharmaceutically Important Morphinan Skeleton
Advanced Synthesis & Catalysis ( IF 4.4 ) Pub Date : 2018-12-07 , DOI: 10.1002/adsc.201801326
Peiyuan Yao _{1,

2,

3} , Zefei Xu _{1,

2} , Shanshan Yu ₂ , Qiaqing Wu _{1,

2} , Dunming Zhu _{1,

2}

Affiliation

The morphinan skeleton is an important sub‐structure in many medicines such as dextromethorphan, and can be constructed from 1‐benzyl‐1,2,3,4,5,6,7,8‐octahydroisoquinoline (1‐benzyl‐OHIQ) derivatives. 1‐Benzyl‐3,4,5,6,7,8‐hexahydroisoquinolines (1‐benzyl‐HHIQs), the precursors of 1‐benzyl‐OHIQs, constitute a type of bulky α, β‐unsaturated imines. Until now, the application of imine reductases (IREDs) to α, β‐unsaturated imines has only rarely been reported. In this study, through evaluation of 48 IREDs, both enantiomers of 1‐(4‐methoxybenzyl)‐1,2,3,4,5,6,7,8‐octahydroisoquinoline (1‐(4‐methoxybenzyl)‐OHIQ) were obtained in high yield and excellent optical purity. Among the enzymes, the most steric hindrance‐tolerant IRED from Sandarearacinus amylolyticus (IR40) was able to convert various phenyl substituted 1‐benzyl‐HHIQ to the corresponding 1‐benzyl‐OHIQ derivatives with excellent enantiometric excess. These results provide an effective route to synthesize these important compounds via enantioselective reduction of bulky α, β‐unsaturated imine precursors, which can be readily prepared from 2‐(1‐cyclohexenyl)ethylamine and corresponding aryl acetic acids.

中文翻译：

亚胺还原酶催化的大块α，β-不饱和亚胺向药学上重要的吗啡骨架的转移

吗啡骨架是许多药物（例如右美沙芬）中的重要子结构，可以由1-苄基1,2,3,4,5,6,7,8-八氢异喹啉（1-苄基OHIQ）衍生物构建。1-苄基-OHIQ的前体1-苄基-3,4,5,6,7,8-六氢异喹啉（1-苄基-HHIQs）构成了一种大体积的α，β-不饱和亚胺。到目前为止，很少有人报道将亚胺还原酶（IRED）应用于α，β-不饱和亚胺。在这项研究中，通过评估48个IRED，1-（4-甲氧基苄基）-1,2,3,4,5,6,7,8-八氢异喹啉（1-（4-甲氧基苄基）-OHIQ）的对映体均为获得高收率和优异的光学纯度。在这些酶中，最能耐受空间位阻的SREDARERANACUS Amylolyticus（IR40）能够将各种苯基取代的1-苄基-HHIQ转化为对映体过量极好的对应的1-苄基-OHIQ衍生物。这些结果提供了通过庞大的α，β-不饱和亚胺前体的对映选择性还原合成这些重要化合物的有效途径，可以很容易地由2-（1-环己烯基）乙胺和相应的芳基乙酸制备这些化合物。

更新日期：2018-12-07

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